The human retrovirus, human immunodeficiency virus (HIV), causes Acquired Immunodeficiency Syndrome (AIDS), an incurable disease in which the body's immune system breaks down leaving the victim vulnerable to opportunistic infections, e.g., pneumonia, and certain cancers, e.g., Kaposi's Sarcoma. AIDS is a major global health problem. The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that there are now over 34 million people living with HIV or AIDS worldwide, some 28.1 million of those infected individuals reside in impoverished sub-Saharan Africa. In the United States, approximately one out of every 500 people are infected with HIV or have AIDS. Since the beginning of the epidemic, AIDS has killed nearly 19 million people worldwide, including some 425,000 Americans. AIDS has replaced malaria and tuberculosis as the world's deadliest infectious disease among adults and is the fourth leading cause of death worldwide.
The molecular mechanism of HIV entry into cells involves specific interactions between the viral envelope glycoproteins (env) and two target cell proteins, CD4 and the chemokine receptors. HIV cell tropism is determined by the specificity of the env for a particular chemokine receptor, a 7 transmembrane-spanning, G protein-coupled receptor (Steinberger et al., (2000) Proc. Natl. Acad. Sci. USA. 97: 805-10). The two major families of chemokine receptors are the CXC chemokine receptors and the CC chemokine receptors (CCR) so named for their binding of CXC and CC chemokines, respectively. While CXC chemokine receptors traditionally have been associated with acute inflammatory responses, the CCRs are mostly expressed on cell types found in connection with chronic inflammation and T-cell-mediated inflammatory reactions: eosinophils, basophils, monocytes, macrophages, dendritic cells, and T cells (Nansen, et al. 2002, Blood 99:4). It has been shown that CC chemokine receptor 5 (CCR5) represents the major co-receptor for primary Macrophage-cell-line-tropic (M-tropic) HIV strains (Deng et al. (1996) Nature 381:661). M-tropic strains predominate during the asymptotic phase of the disease in infected individuals (Samson, et al. (1996) Nature 382:722). Eventually, however, HIV can become dual-tropic. Such strains are capable of recognizing the CXCR4 protein on CD4-bearing T-cells. During this phase HIV-1 may infect both macrophages and T-cells. Still later, the bulk of the viral population may switch it's preference to the CXCR4 receptor and become T-cell-line-tropic (T-tropic). T-tropic viruses readily destroy infected T-cells, contributing to the collapse of the immune system and the onset of AIDS which leads to opportunistic infections, neurological disease, neoplastic growth and eventual death.